Autosomal recessive macular dystrophies caused by mutations in the ABCA4 gene, STGD1, CRD, RP, etc., are together the most prevalent Mendelian inherited cause of vision loss in both children and adults. Importantly, 5% (1:20) of the general population carry a disease-associated ABCA4 allele although not all combinations of variants are fully penetrant. Despite extensive genetic variability, several mutations account for large fractions of the disease and often result in specific, discernable sub-phenotypes. The most frequent disease-associated ABCA4 allele, p.G1961E, is a causal mutation in 20% to 50% of patients amongst ethnically different populations. When present in either compound heterozygous or homozygous state it results in a very consistent phenotype characterized by early ablation of foveal cones, but otherwise slow progression and the absence or moderate expression of the major consequence of ABCA4 protein dysfunction, lipofuscin accumulation. Another recently identified common disease allele, p.N1868I, is present in ~7% in the general population and represents an ?extremely? hypomorphic allele, which is causal only when in trans with a deleterious allele. Patients harboring p.N1968I also exhibit no significant lipofuscin accumulation, slow disease progression and disease changes similar to p.G1961E. However, in contrast to p.G1961E patients, p.N1868I is highly associated with the ?foveal sparing? phenotype, i.e., preservation of foveal cones during the course of the disease. Since lipofuscin accumulation, and consequent RPE toxicity, is the common therapeutic target for ABCA4 disease, existing data suggest that such interventions may have no applicability for patients harboring p.G1961E and p.N1861I as causal variants. Elucidating the functional consequences of these two variants would direct treatment options for up to half of affected individuals with ABCA4 disease. The proposed research strategy utilizes complementary clinical and functional methodology and is organized into two Specific Aims. In the first Aim, we propose using our existing genetic and clinical databases, accumulated knowledge, and a combination of advanced imaging methods and functional testing to determine precise, quantifiable differences between patients with hypomorphic alleles and other deleterious alleles. In the second Aim we will determine the functional consequences of the hypomorphic ABCA4 mutations on protein function by a combination of studies, which determine the mutant protein structure, localization, transport and ATPase activity, in iPSC-derived patient cell cultures and mouse models. The outcome of these studies will substantially aid in disease diagnosis, prognosis and will serve as a platform for designing clinical trials for a significant fraction of ABCA4 disease.